A single dose of the beta-adrenergic antagonists propranolol and atenolol decreases blood pressure (BP) in conscious spontaneously hypertensive (SH) rats. Unlike the decreases in BP caused by the peripheral vasodilator minoxidil, the drop in BP caused by these beta-adrenergic antagonists is not accompanied by an increase in plasma norepinephrine (NE) concentration. Also, the prostaglandin synthetase inhibitor indomethacin impairs the ability of propranolol to lower BP in SH rats. I hypothesize that beta-adrenergic antagonists lower BP in the SH rats by decreasing the release of NE from peripheral sympathetic neurons via a prostaglandin-dependent mechanism. To test this hypothesis, I will assess the ability of a single dose of the beta-adrenergic antagonists propranolol, pindolol, sotalol, practolol, atenolol, betaxolol and ICI 118,551 to alter the apparent neuronal secretion rate of NE and the rate of clearance of NE from plasma in conscious SH rats as related to the time-course of their antihypertensive effects. These NE release and clearance values can be determined by the i.v. infusion of 3H-levo-NE to a steady-state concentration and relating the amount of 3H-NE and the specific activity of NE in the plasma to the rate of infusion. In addition, the ability of the prostaglandin synthetase inhibitors indomethacin and sodium meclofenamate to reverse the antihypertensive and proposed sympathetic neuronal effects of these beta-adrenergic antagonists will be determined. Beta-adrenergic antagonists are effective antihypertensive agents in humans, but the mechanism by which they lower BP is unknown. These studies will help to identify or eliminate the sympathetic neuron as an antihypertensive site of action of beta-adrenergic antagonists.